TimTec Diversity Library of 10,000 compounds was screened in research collaboration between Department of Veterinary Molecular Biology at Montana State UniVersity, Bozeman, Montana, and Department of Chemistry at Altai State Technical UniVersity, Barnaul, Russia.
Published screening results identified 18 hit compounds, most potent inhibitors of Anthrax Lethal Factor.
Schepetkin, I., et al., Novel Small-molecule Inhibitors of Anthrax Lethal Factor Identified by High-throughput Screening. J. Med. Chem. 49: 5232-5244 (2006)
Abstract
Anthrax lethal factor (LF) is a key virulence factor of anthrax lethal toxin. We screened a chemolibrary of 10 000 drug-like molecules for their ability to inhibit LF and identified 18 novel small molecules with potent LF inhibitory activity. Three additional LF inhibitors were identified through further structureactivity
relationship (SAR) analysis. All 21 compounds inhibited LF with an IC50 range of 0.8 to 11 ÃÂM, utilizing mixed-mode competitive inhibition. An evaluation of inhibitory activity against a range of unrelated proteases showed relatively high specificity for LF. Furthermore, pharmacophore modeling of these
compounds showed a high degree of similarity to the model published by Panchal et al. (Nat. Struct. Mol. Biol. 2004, 11, 67-72), indicating that the conformational features of these inhibitors are structurally compatible with the steric constraints of the substrate-binding pocket. These novel LF inhibitors and the structural scaffolds identified as important for inhibitory activity represent promising leads to pursue for further LF inhibitor development.
Activators of Neutrophils analogs
Inhibitors of Anthrax Lethal Factor
ST003272 C10H8N2O3S 236.25 |
ST018515 C15H12O6 288.26 |
ST019413 C17H12N4O5S2 416.44 |
ST020475 C21H13ClN2O5 408.8 |
ST020488 C21H19ClN2O3 382.85 |
ST024040 C24H18ClN3O5S2 528.01 |
ST028252 C22H14Cl2N2O4 441.27 |
ST028971 C14H12BrNO4S2 402.29 |
ST032629 C18H11N3O5S2 413.43 |
ST037827 C18H13N3O5S 383.38 |
ST040452 C17H16ClN5O3S2 437.93 |
ST042011 C23H12BrF3N2O6 549.26 |
ST042187 C13H13NO3 231.25 |
ST072610 C24H15ClN2O5S2 510.98 |
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